Pharmacotherapy of Pediatric Hypertension

FDA Corner

Mona Khurana, MD, Pediatric Team LeaderDivision of Pediatric and Maternal Health

Office of New DrugsCenter for Drug Evaluation and Research

Food and Drug Administration

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Outline• Landscape of Approved Drugs for Pediatric

Hypertension• Basis for Pediatric Approval• Challenges and Knowledge Gaps

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Disclosure Statement• I am employed by the US Food and Drug

Administration and I have no financial relationships to disclose relating to this presentation.

• The views expressed in this talk represent my opinions and do not necessarily represent the views of FDA.

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Currently Approved Pediatric Antihypertensive Drugs

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Currently Approved Pediatric Antihypertensive Drugs

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Initial Approach to Drug Approval• 2002 pediatric approval of enalapril > age 1 month*

– Extrapolation of adult efficacy – Multiple-dose (0.07-0.14 mg/kg/day) PK study in 40

hypertensive patients age 2 months to 16 years• Consistent PK profile across all ages studied

– Dose-ranging trial in 110 hypertensive patients age 6-16 years showed dose-dependent BP reduction

• < 50 kg: 0.625, 2.5, or 20 mg/day• > 50 kg: 1.25, 5, or 40 mg/day

• Subsequent data for other drugs showed no efficacy in pediatric age groups despite PK similarity to adults

*FDA Approved Vasotec Labeling (accessed from Drugs@FDA 2/9/20)

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Current Approach to Drug Approval • > 1 pediatric pharmacokinetic studies • Single controlled pediatric efficacy trial

– Double-blind, randomized dose-ranging trial + placebo – Randomized withdrawal trial

• Lead-in period of < 10 days• Initial randomization phase into > 2 active treatment arms (low,

medium, high dosage)• Second randomization to double-blind withdrawal to active

drug vs. placebo• Open-label safety phase• Change in systolic or diastolic blood pressure as primary

efficacy measure (validated surrogate endpoint)

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Basis for Pediatric Approval

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Other Approaches to Drug Approval• Reduce mean 10-year lag period between adult

and pediatric approval• Prevent off-label pediatric use post-approval in

adults• Leverage existing adult and pediatric (e.g. > age

6 years) clinical trial data from approved drugs to determine what additional data would be needed in target pediatric population (e.g. < age 6 years)

July 20, 2017 Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population

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Extrapolation Approaches in Pediatric Programs

Increasing level of confidence in similarity of

disease/response

Increasing level of evidence

required from pediatric studies

~60% Pediatric Programsrequire at least 1 adequate, well-controlled efficacy trial (clinical or surrogate endpoint)

1 or more adequate-well controlled studies powered on a surrogate endpointDiabetes, anemia, idiopathic thrombocytopenia, treatment of venous thromboembolism, hypertension, hypercholesterolemia, asthma, etc.

1 or more adequate-well controlled studies powered on a clinically meaningful endpointBipolar disorder, systemic juvenile idiopathic arthritis, major depression, migraine, polyarticular JIA (pJIA), bronchopulmonary dysplasia, ADHD, nausea/vomiting, partial seizures (<4 y/o), respiratory syncytial virus, prophylaxis of venous thromboembolism, atopic dermatitis, etc.

Descriptive efficacy study without concurrent controlPlaque psoriasis, Neurogenic detrusor over-activity, pJIA (NSAIDs), etc.

Controlled study without formal statistical powerCommunity acquired pneumonia, nosocomial infections, skin and skin structure infections, etc.

PK/safety only (single dose level matching adult exposures)gastroesophageal reflux disease, bacterial sinusitis, herpes simplex, analgesics/anesthetics (well known MOAs; over 2 y/o), imaging products, melanoma (adolescents)

Small dose-ranging studies (randomization to multiple dose levels) Sedation, ulcerative colitis, Crohn’s, etc.

Small PK/PD studies (single dose level matching adult exposures)HIV, erosive esophagitis (infants), anesthetics, pulmonary arterial hypertension,

List partially adapted from Dunne et al. Pediatrics 2011

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Data Gaps• Only 2 drugs approved for oral use in patients

less than 6 years of age and none in neonates– Enalapril approved down to age 1 month – Candesartan approved down to age 1 year

• Need for more age-appropriate formulations with known bioavailability – Dosing flexibility– Dosing accuracy

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Failed Trials: Possible Contributing Factors

• Poor dose selection– Narrow dosage range studied– Exposure-response relationship presumed to be similar

between adults and pediatrics• Lack of age-appropriate formulation with

demonstrated bioequivalence to approved dosage form

• Choice of primary efficacy endpoint• Blood pressure measurement technique

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References• Momper JD, Mulugeta Y, Burckart GJ. Failed

Pediatric Drug Development Trials. Clinical Pharmacology & Therapeutics 98(3), 2015.

• Benjamin DK, Smith PB, Jadhav P, et al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose Range. Hypertension 51: 834-840, 2008.